In Veterans, gambling disorder (GD) is at least twice as prevalent as in the general public, and it is associated with devastating outcomes including suicidal attempts in up to 43% of the patients. However, little is known about the neurobiological mechanisms underlying this disorder while such knowledge may be vital for the development of successful therapeutic interventions. Drug addiction models have heuristic value in this regard as GD is classified among Substance-Related and Addictive Disorders in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition. Both drug and gambling addiction are characterized by decreased sensitivity to natural reinforcers and stress-like emotional states. In drug addiction, such symptomatology has been attributed to respective reward deficiency and anti-reward allostatic neuroadaptations. In the present proposal we seek to determine whether similar neuroadaptations exist in GD by integrating functional magnetic resonance imaging (fMRI), cognitive psychology and psychopharmacology to measure reward and stress responses in 40 Veterans with GD and in 40 healthy Veterans. As a second comparison group, we will enroll 40 Veterans with cocaine use disorder (CUD) matched to the GD group by the addiction severity. Three experimental procedures on this project include: (a) evoking social reward and stress by visual processing of rewarding and stressful images, (b) intravenous administration of yohimbine, a noradrenergic agent that reliably increases physiological and psychological stress responses and (c) monetary reward incorporated into a gambling task. Our preliminary data using these procedures to compare GD and healthy subjects identified unique patterns of fMRI signal changes in the ventral tegmentum, nucleus accumbens, amygdala, orbitofrontal cortex and sublenticular extended amygdala along with related structures during reward and stress processing. In the proposed experiments, it is predicted that, in comparison to healthy controls, Veterans with GD and CUD will exhibit diminished and exaggerated responses in the domains of rewarding and stressful stimuli, respectively. The impairments in the GD group are expected to be less prominent consistent with more severe deleterious effects of chronic cocaine exposure. An association is also predicted between those neural responses and clinical characteristics of GD and CUD. Our finding will allow understanding the distinctive features of behavioral addiction, GD, vis--vis those of a substance addiction, CUD, and their unique contribution to the common addictive process. In addition to providing important leads for understanding and preventing the development of GD particularly in the context of chronic stress exposure, our project will offer insights on the pathogenesis of emotional numbing and stress sensitivity symptoms, which cause severe disability not only in addicted patients, but also in those suffering from other neuropsychiatric conditions such as post-traumatic stress disorder, schizophrenia and major depression.